FDA Device Oversight Slammed

The FDA's regulation of medical device safety is woefully inadequate, potentially contributing to hundreds of deaths in the case of one device in particular, two journalists charged.

The journalists, Jeanne Lenzer and Shannon Brownlee, reported online in BMJ that more than 900 deaths have been reported in patients implanted with a vagus nerve stimulator approved in 1997 for treatment-resistant partial seizures. Yet the device -- manufactured by Cyberonics and sold as the VNS Therapy System -- remains on the market.

Neither the manufacturer nor the FDA have attempted a systematic investigation of the system's role, if any, in the deaths, Lenzer and Brownlee reported.

"Although Cyberonics conducted post-approval studies, none of the studies submitted to the FDA included mortality data. The FDA did not specifically require Cyberonics to submit mortality data as part of the follow-up study, merely to 'characterize morbidity and mortality,'" they wrote.

The FDA told them that it had not requested additional mortality data from Cyberonics, the journalists indicated. They reported that officials had pointed them to five postmarketing safety studies of the VNS system, which the agency found acceptable even though they lacked data on deaths specifically.

In response to the BMJ article, Cyberonics issued a statement asserting that none of the 900 deaths was attributable to the device.

"Available data demonstrate that all-cause mortality rates for VNS Therapy patients are less than half the rates in the comparable non-VNS epilepsy patient population (6.8 vs. 14-19 per 1,000-patient years)," the statement said.

Cyberonics said this information was provided to Lenzer and Brownlee but omitted from their article.

Most of the journalists' report dealt with the FDA and its postmarketing requirements. They charged that the FDA's lack of aggressive follow-up in this case "is but one example of the gap in post-approval surveillance of medical devices."

In an accompanying editorial, Jerry Avorn, MD, of Harvard Medical School in Boston, agreed that the FDA does a poor job of assuring device safety.

"The standards for device approval and surveillance have fallen far below those for drugs, and even those that would be dictated by common sense," Avorn wrote.

"It would be unthinkable for a drug company to go to the [FDA] or the European Medicines Agency and say, in effect, 'This new drug is much like an older product we sell, except that we have added a new amine group and modified one of the side chains. Apart from that, it's pretty close, so we won't be doing any new clinical tests on it. When can we begin marketing?' But this is essentially what happens with many new medical devices when they are approved," according to Avorn.

The VNS Therapy device is not the first to become a focus for criticism of the FDA's regulation of devices. In August, for example, MedPage Today reported on problems with a spinal fusion device based on bone morphogenetic protein-2 -- touted as a near-miracle treatment for disc degeneration but which subsequently appeared to produce life-threatening complications in some patients.

The agency also faced attacks for the process by which it approved a meniscal replacement implant for damaged knees, called Menaflex. Congressional investigators and an internal FDA probe found that top officials in the agency, including the commissioner, had pressured the professional staff to give the device positive reviews.

In the case of the Cyberonics vagus nerve stimulator, the paucity of data leave it unclear whether the device is contributing to fatalities or whether the deaths are simply a consequence of severe epilepsy.

A condition called sudden unexpected death from epilepsy, or SUDEP, is well known. One study of patients with treatment-resistant epilepsy found a SUDEP rate of about 0.9%.

Cyberonics' clinical trial data submitted in 1997 indicated a death rate of 0.7% in patients receiving the device, with SUDEP listed as the most common cause.

The company told the journalists that some 57,000 devices had been implanted worldwide, although an unknown number may have subsequently been deactivated or removed.

As a condition of approval, the FDA ordered Cyberonics to conduct a follow-up safety study and to report all serious adverse outcomes. The study was completed, but it did not include specific data on mortality. The 900 reports of fatalities in implanted patients have not moved the FDA to pursue additional investigations.

Lenzer and Brownlee, reviewing reports in the FDA's MAUDE system for adverse event reporting on devices, identified several that noted the presence of asystole and/or bradycardia, or other symptoms consistent with these cardiac abnormalities. They reported that at least one survivor of repeated such episodes stopped having them when the VNS device was turned off.

These reports "ostensibly should have prompted further investigation by the FDA," the journalists wrote.

The journalists, and Avorn, decried MAUDE as much less useful than its sister system on the drugs side, AERS.

They noted that MAUDE has few requirements or standards for reports to follow. Lenzer and Brownlee found one fatality report on a patient with a VNS Therapy System implant that mentioned a "visual autopsy" as the basis for conclusions on the cause of death.

"Most MAUDE death reports, which are mainly written by manufacturers, contain descriptions so brief that no definitive cause of death can be inferred," they wrote.

In his editorial, Avorn noted that recordkeeping for device implants is often extremely minimal. "A researcher or regulator can readily identify all the drugs the person was taking before the procedure, but a detailed definition of the device itself is not routinely recorded in most clinical databases," he wrote.

Avorn observed that the leadership of the FDA's devices division had recently been changed, "which is a welcome development."

But Avorn recommended that the new regime institute a more sweeping overhaul, starting with abandonment of the "substantial equivalence" standard for clearing new products under the so-called 510(k) process.

He also called for "better requirements in place for clinical review of new products, as was done for drugs in response to the thalidomide disaster of the early 1960s."

The FDA has taken a small step in that direction, proposing that applicants for so-called fast-track 510(k) approvals be required to submit more detailed product-specific safety and efficacy data.

A third recommendation from Avorn was to revamp the MAUDE system to function more like AERS and similar systems in Great Britain and the Netherlands for reporting and analyzing adverse drug events, Avorn indicated.

Finally, he recommended that postmarketing safety reviews be conducted by an FDA unit separate from the office that grants approvals.

"The disappointing history of device regulation reminds us that it is not wise to allow the safety of a medical intervention to be judged primarily by the people who approved it and the companies that manufacture it," Avorn wrote.

Lenzer, Brownlee, and Avorn declared they had no financial conflicts of interest.

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